The Promise of Mutation Resistant Drugs for SARS-CoV-2 That Interdict in the Folding of the Spike Protein Receptor Binding Domain
Abstract
:1. Introduction
2. Results
2.1. The Receptor Binding Domain of the Spike Protein of SARS-CoV-2
2.2. Primary Contacts for RBD-Spike Mutants
2.3. Effects of Mutation A435S
2.4. Effects of Mutation W436R
3. Discussion
4. Methods: The SCM Model
4.1. The SCM Entropic Cost of Loop Formation
4.2. Determining the Primary Contact
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
- Carlson, C.J.; Phelan, A.L. A choice between two futures for pandemic recovery. Lancet Planet. Health 2020, 4, E545–E546. [Google Scholar] [CrossRef]
- Hiscott, J.; Alexandridi, M.; Muscolini, M.; Tassone, E.; Palermo, R.; Soultsioti, M.; Zevini, A. The global impact of the coronavirus pandemic. Cytokine Growth Factor Revs. 2020, 53, 1–9. [Google Scholar] [CrossRef]
- Impact of the COVID-19 pandemic on trade and development: Transitioning to a new normal. In Proceedings of the United Nations Conference on Trade and Development, New York, NY, USA, 19 November 2020.
- Kemp, S.A.; Collier, D.A.; Gupta, R.V. SARS-CoV-2 evolution during treatment of chronic infection. Nature 2021, 592, 277–282. [Google Scholar] [CrossRef] [PubMed]
- Williams, T.C.; Burgers, W.A. SARS-CoV-2 evolution and vaccines: Cause for concern? Lancet Respir. Med. 2021, 9, 333–335. [Google Scholar] [CrossRef]
- Moore, J.P.; Offit, P.A. SARS-CoV-2 vaccines and the growing threat of viral variants. JAMA 2021, 325, 821–822. [Google Scholar] [CrossRef]
- Korber, B.; Fischer, W.M.; Gnanakaran, S.; Yoon, H.; Theiler, J.; Abfalterer, W.; Hengartner, N.; Giorgi, E.E.; Bhattacharya, T.; Foley, B.; et al. Tracking changes in SARS-CoV-2 spike: Evidence that D614G increases infectivity of the COVID-19 virus. Cell 2020, 182, 812–827. [Google Scholar] [CrossRef]
- Islam, M.R.; Hoque, M.N.; Rahman, M.S.; Rubayet Ul Alam, A.S.M.; Akther, M.; Puspo, J.A.; Akter, S.; Sultana, M.; Crandall, K.A.; Hossain, M.A. Genome-wide analysis of SARS-CoV-2 virus strains circulating worldwide implicates heterogeneity. Nature Sci. Reps. 2020, 10, 14004. [Google Scholar] [CrossRef] [PubMed]
- Tang, J.W.; Tambyah, P.A.; Hui, D.S. Emergence of a new SARS-CoV-2 variant in the UK. J. Infect. 2021. [Google Scholar] [CrossRef] [PubMed]
- Tegally, H.; Wilkinson, E.; Giovanetti, M.; Iranzadeh, A.; Fonseca, V.; Giandhari, J.; Doolabh, D.; Pillay, S.; San, E.J.; Msomi, N.; et al. Emergence and rapid spread of a new severe acute respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. Medxirv 2020. [Google Scholar] [CrossRef]
- Bernal, J.L.; Andrews, N.; Gower, C.; Gallagher, E.; Simmons, R.; Thelwall, S.; Stowe, J.; Tessler, E.; Groves, N.; Dabrera, G.; et al. Effectiveness of COVID-19 vaccines against the B.1.617.2 variant. Medrxiv 2021. [Google Scholar] [CrossRef]
- Holland, J.J.; Drake, J.W. Mutation rates among RNA viruses. PNAS USA 1999, 96, 13910–13913. [Google Scholar]
- Bergasa-Caceres, F.; Rabitz, H.A. Interdiction of protein folding for therapeutic drug development in SARS-CoV-2. J. Phys. Chem. B 2020, 124, 8201–8208. [Google Scholar] [CrossRef] [PubMed]
- Li, F. Receptor recognition mechanisms of coronaviruses: A decade of structural studies. J. Virol. 2015, 89, 1954–1964. [Google Scholar] [CrossRef] [Green Version]
- Li, W.H.; Greenough, T.C.; Moore, M.J.; Vasilieva, N.; Somasundaran, M.; Sullivan, J.L.; Farzan, M.; Choe, H. Efficient replication of severe acute respiratory syndrome coronavirus in mouse cells is limited by murine angiotensin-converting enzyme. J. Virol. 2004, 78, 11429–11433. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, F.; Li, W.H.; Farzan, M.; Harrison, S.C. Structure of SARS coronavirus spike receptor binding domain complexed with receptor. Science 2005, 309, 1664–1668. [Google Scholar] [CrossRef] [PubMed]
- Du, L.; He, Y.; Zhou, Y.; Liu, S.; Zheng, B.-J.; Jiang, S. The spike protein of SARS-CoV: A target for vaccine and therapeutic development. Nat. Rev. Microbiol. 2009, 7, 226–236. [Google Scholar] [CrossRef]
- Shang, J.; Ye, G.; Shi, K.; Wan, Y.; Luo, C.; Aihara, H.; Geng, Q.; Auerbach, A.; Li, F. Structural basis of receptor recognition by SARS-CoV-2. Nature 2020, 581, 221–224. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bergasa-Caceres, F.; Ronneberg, T.A.; Rabitz, H.A. Sequential collapse model for protein folding pathways. J. Phys. Chem. B 1999, 103, 9749–9758. [Google Scholar] [CrossRef]
- Bergasa-Caceres, F.; Haas, E.; Rabitz, H.A. Nature’s shortcut to protein folding. J. Phys. Chem. B 2019, 123, 4463–4476. [Google Scholar] [CrossRef]
- Motta, A.; Reches, M.; Pappalardo, L.; Andreotti, G.; Gazit, E. The preferred conformation of the tripeptide ala-phe-ala in water is an inverse γ-turn: Implications for protein folding and drug design. Biochemistry 2005, 44, 14170–14178. [Google Scholar] [CrossRef]
- Broglia, R.A.; Serrano, L.; Tiana, G. (Eds.) Protein Folding and Drug Design. In Proceedings of the International School of Physics “Enrico Fermi”, 165; IOS Press: Amsterdam, The Netherlands, 2007. [Google Scholar]
- Das, A.; Yadav, A.; Gupta, M.; Purushotham, R.; Terse, V.L.; Vishvakarma, V.; Singh, S.; Nandi, T.; Mandal, K.; Gosavi, S.; et al. Rational design of protein-specific folding modifiers. bioRxiv 2020. [Google Scholar] [CrossRef]
- Spagnolli, G.; Massignan, T.; Astolfi, A.; Biggi, S.; Rigoli, M.; Brunelli, P.; Libergoli, M.; Ianeselli, A.; Orioli, S.; Boldrini, A. Pharmacological inactivation of the prion protein by targeting a folding intermediate. Nat. Comm. Biol. 2021, 4, 62. [Google Scholar] [CrossRef]
- Massignan, T.; Boldrini, A.; Terruzzi, L.; Spagnoli, G.; Astolfi, A.; Bonaldo, V.; Pischedda, F.; Pizzato, M.; Lolli, G.; Barreca, M.L. Antimalarial Artefenomel Inhibits Human sars-cov-2 Replication In Cells While Supressing The Receptor ACE2. arXiv 2021, 2004, 13493v4. [Google Scholar]
- Walls, A.C.; Park, Y.-J.; Tortorici, M.A.; Wall, A.; McGuire, A.T.; Veesler, D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020, 181, 281–292. [Google Scholar] [CrossRef] [PubMed]
- Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.H.; Nitsche, A.; et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020, 181, 271–280. [Google Scholar] [CrossRef] [PubMed]
- Tortorici, M.A.; Veesler, D. Structural insights into coronavirus entry. Adv. Virus Res. 2019, 105, 93–116. [Google Scholar] [PubMed]
- Greaney, A.J.; Starr, T.N.; Gilchuk, P.; Zost, S.J.; Binshtein, E.; Loes, A.N.; Hilton, S.K.; Hudleston, J.; Eguia, R.; Crawford, K.H.D.; et al. Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition. Cell Host Microbe 2021, 29, 44–57. [Google Scholar] [CrossRef]
- Li, W.H.; Moore, M.J.; Vasilieva, N.; Sui, J.H.; Wong, S.K.; Berne, M.A.; Somasundaran, M.; Sullivan, J.L.; Luzuriaga, K.; Greenough, T.C.; et al. Angiotensin-converting Enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003, 426, 450–454. [Google Scholar] [CrossRef] [Green Version]
- Hatmal, M.M.; Alshaer, W.; Hatamleh, M.A.I.; Hatmal., M.; Smadi, O.; Taha, M.O.; Oweida, A.J.; Boer, J.C.; Mohamud, R.; Plebanski, M. Comprehensive Structural and Molecular Comparison of Spike Proteins of SARS-CoV-2, SARS-CoV and MERS-CoV and Their Interaction with ACE2. Cells 2020, 9, 2638. [Google Scholar] [CrossRef]
- Brown, E.E.F.; Rezaei, R.; Jamieson, T.R.; Dave, J.; Martin, N.T.; Singaravelu, R.; Crupi, M.J.F.; Boulton, S.; Tucker, S.; Duong, J.; et al. Characterization of critical determinants of ACE2-SARS CoV-2 RBD interaction. Int. J. Mo. Sci. 2021, 22, 2268. [Google Scholar] [CrossRef]
- Premkumar, L.; Segovia-Chumbez, B.; Jadi, R.; Martinez, D.R.; Raut, R.; Markmann, A.J.; Cornaby, C.; Bartelt, L.; Weiss, S.; Park, Y.; et al. The receptor-binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients. Sci. Immunol. 2020, 5, eabc8413. [Google Scholar] [CrossRef] [PubMed]
- Hu, H.; Li, L.; Kao, R.Y.; Kou, B.; Wang, Z.; Zhang, L.; Zhang, H.; Hao, Z.; Tsui, W.H.; Ni, A.; et al. Screening and identification of linear B-cell epitopes and entry-blocking peptide of Severe Acute Respiratory Syndrome (SARS)-associated coronavirus using synthetic overlapping peptide library. J. Comb. Chem. 2005, 7, 648–656. [Google Scholar] [CrossRef]
- Keng, C.T.; Zhang, A.; Shen, S.; Lip, K.M.; Fielding, B.C.; Tan, T.H.; Chou, C.-F.; Loh, C.B.; Wang, S.; Fu, J.; et al. Amino acids 1055 to 1192 in the S2 region of severe acute respiratory syndrome coronavirus S protein induce neutralizing antibodies: Implications for the development of vaccines and antiviral agents. J. Virol. 2005, 79, 3289–3296. [Google Scholar] [CrossRef] [Green Version]
- Wu, Y.; Wang, C.; Shen, W.; Peng, D.; Li, C.; Zhao, Z.; Li, S.; Li, Y.; Bi, Y.; Yang, Y.; et al. A non-competing pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2. Science 2020, 368, 1274–1278. [Google Scholar] [CrossRef] [PubMed]
- Yuan, M.; Liu, H.; Wu, N.C.; Lee, C.-C.D.; Zhu, X.; Zhao, F.; Wang, D.; Yu, W.; Hua, Y.; Tien, H.; et al. Structural basis of a shared antibody response to SARS-CoV-2. Science 2020, 369, 1119–1123. [Google Scholar] [CrossRef] [PubMed]
- Esparza, T.J.; Martin, N.P.; Anderson, G.P.; Goldman, E.R.; Brody, D.L. High affinity nanobodies block SARS-CoV-2 spike receptor binding domain interaction with human angiotensin converting enzyme. Nature Sci. Rep. 2020, 10, 22370. [Google Scholar]
- Kim, S.I.; Noh, J.; Kim, S.; Choi, Y.; Yoo, D.K.; Lee, Y.; Lee, H.; Jung, J.; Kang, C.K.; Song, K.-H.; et al. Stereotypic neutralizing antibodies against SARS-CoV-2 spike protein receptor binding domain in patients with COVID-19 and healthy individuals. Sci. Trans. Med. 2021, 13, eabd6990. [Google Scholar] [CrossRef] [PubMed]
- Han, Y.; Král, P. Computational design of ACE-2-based peptide inhibitors of SARS-CoV-2. ACS Nano 2020, 14, 5143–5147. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Maiti, B.K. Potential role of peptide-based antiviral therapy against SARS-CoV-2 infection. ACS Pharmacol. Transl. Sci. 2020, 3, 783–785. [Google Scholar]
- Karoyan, P.; Vieillard, V.; Gómez-Morales, L.; Odile, E.; Guihot, A.; Luyt, C.-E.; Denis, A.; Grondin, P.; Lequin, O. Human ACE2 peptide-mimics block SARS-CoV-2 pulmonary cells infection. Nat. Commun. Biol. 2021, 4, 197. [Google Scholar] [CrossRef]
- Padhi, A.K.; Tripathi, T. Can SARS-CoV-2 accumulate mutations in the S-protein to increase pathogenicity? ACS Pharmacol. Transl. Sci. 2020, 3, 1023–1026. [Google Scholar] [CrossRef]
- Li, Q.; Wu, J.; Nie, J.; Zhang, L.; Hao, H.; Liu, S.; Zhao, C.; Zhang, Q.; Liu, H.; Nie, L.; et al. The impact of mutations in SARS-CoV-2 spike on viral infectivity and antigenicity. Cell 2020, 182, 1284–1294. [Google Scholar] [CrossRef] [PubMed]
- Ou, J.; Zhou, Z.; Dai, R.; Zhao, S.; Wu, X.; Zhang, J.; Lan, W.; Cui, L.; Wu, J.; Seto, D.; et al. Emergence of SARS-CoV-2 spike RBD mutants that enhance viral infectivity through increased human ACE2 receptor binding affinity. bioRxiv 2020. [Google Scholar] [CrossRef] [Green Version]
- Rambaut, A.; Loman, N.; Pybus, O.; Barclay, W.; Barrett, J.; Carabelli, A.; Connor, T.; Peacock, T.; Robertson, D.L.; Volz, E.; et al. Preliminary genomic characterization of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations. Available online: https://virological.org/t/preliminary-genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-the-uk-defined-by-a-novel-set-of-spike-mutations/563 (accessed on 9 December 2020).
- Khan, A.; Zia, T.; Suleman, M.; Khan, T.; Ali, S.S.; Abbasi, A.A.; Mohammad, A.; Wei, D.-Q. Higher infectivity of the SARS-CoV-2 new variant is associated with K417N/T, E484K, and N501Y mutants: An insight from structural data. J. Cell. Physiol. 2021, 1–13. [Google Scholar] [CrossRef]
- Luan, B.; Wang, H.; Huynh, T. Enhanced binding of the N501Y-mutated SARS-CoV-2 spike protein to the human ACE2 receptor: Insights from molecular dynamics simulations. FEBS Lett. 2021, 595, 1454–1461. [Google Scholar] [CrossRef]
- Sikora, M.; von Bülow, S.; Blanc, F.E.C.; Gecht, M.; Covino, R.; Hummer, G. Computational epitope map of SARS-CoV-2 spike protein. PLoS Comp. Biol. 2021, 17, e1008790. [Google Scholar] [CrossRef]
- Yuan, M.; Wu, N.C.; Zhu, X.; Lee, C.C.D.; So, R.T.; Lv, H.; Mok, C.K.; Wilson, I.A. A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV. Science 2020, 368, 630–633. [Google Scholar] [CrossRef] [Green Version]
- Yi, C.; Sun, X.; Ye, J.; Ding, L.; Liu, M.; Yang, Z.; Lu, X.; Zhang, Y.; Ma, L.; Gu, W. Key residues of the receptor binding motif in the spike protein of SARS-CoV-2 that interact with ACE2 and neutralizing antibodies. Nat. Cell. Mol. Immunol. 2020, 17, 621–630. [Google Scholar] [CrossRef]
- Lan, J.; Ge, J.; Yu, J.; Shan, S.; Zhou, H.; Fan, S.; Zhang, Q.; Shi, X.; Wang, Q.; Zhang, L.; et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020, 581, 215–220. [Google Scholar] [CrossRef] [Green Version]
- Georgoulia, P.S.; Glykos, N.M. Molecular simulation of peptides coming of age: Accurate prediction of folding, dynamics and structure. Arch. Biochem. Biophys. 2019, 664, 76–88. [Google Scholar] [CrossRef]
- Geng, H.; Chen, F.; Ye, J.; Jiang, F. Applications of molecular dynamics simulation in structure prediction of peptides and proteins. Comp. Struct. Biotech. J. 2019, 17, 1162–1170. [Google Scholar] [CrossRef] [PubMed]
- Wen, J.; Batabyal, D.; Knutson, N.; Lord, H.; Wikström, M. A comparison between emerging and current biophysical methods for the assesment of higher-order structure of biopharmaceuticals. J. Pharma. Sci. 2020, 109, 247–253. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chan, K.K.; Dorosky, D.; Sharma, P.; Abbasi, S.A.; Dye, J.M.; Kranz, D.M.; Herbert, A.S.; Procko, E. Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2. Science 2020, 369, 1261–1265. [Google Scholar] [CrossRef]
- Yang, Y.W.; Gruebele, M. Folding at the speed limit. Nature 2003, 423, 193–197. [Google Scholar] [CrossRef]
- Samatova, E.; Daberger, J.; Liutkut, M.; Rodnina, M.V. Translational control by ribosome pausing in bacteria: How a non-uniform pace of translation affects protein production and folding. Front. Microbiol. 2021, 11, 619430. [Google Scholar] [CrossRef] [PubMed]
- Vanzi, F.; Vladimirov, S.; Knudsen, C.R.; Goldman, Y.E.; Cooperman, B.S. Protein synthesis by single ribosomes. RNA 2003, 9, 1174–1179. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Aschwanden, C. Why herd immunity for covid is probably impossible. Nature 2021, 591, 520–522. [Google Scholar] [CrossRef]
- Dunker, A.K.; Lawson, J.D.; Brown, C.J.; Williams, R.M.; Romero, P.; Oh, J.S.; Oldfield, C.J.; Campen, A.M.; Ratliff, C.M.; Hipps, K.W.; et al. Intrinsically disordered protein. J. Mol. Graph. Model. 2001, 19, 26–59. [Google Scholar] [CrossRef] [Green Version]
- Conrad, J.C.; Flory, P.J. Moments and distribution functions for polypeptide chains. Poly-L-alanine. Macromolecules 1976, 9, 41–47. [Google Scholar] [CrossRef]
- Jacobson, H.; Stckmeyer, W.H. Intramolecular reactions in polycondensations. I. The theory of linear systems. J. Chem. Phys. 1950, 18, 1600–1607. [Google Scholar] [CrossRef]
- Plotkin, S.S.; Onuchic, J.N. Structural and energetic heterogeneity in protein folding. I. Theory. J. Chem. Phys. 2002, 116, 5263–5283. [Google Scholar] [CrossRef] [Green Version]
- Bergasa-Caceres, F.; Rabitz, H.A. Low entropic barrier to the hydrophobic collapse of the prion protein: Effects of intermediate states and conformational flexibility. J. Phys. Chem. A 2010, 114, 6978–6982. [Google Scholar] [CrossRef] [PubMed]
- Karplus, M.; Weaver, D.L. Diffusion–collision model for protein folding. Biopolymers 1979, 18, 1421–1437. [Google Scholar] [CrossRef]
- Sali, A.; Shakhnovich, E.; Karplus, M. How does a protein fold? Nature 1994, 369, 248–251. [Google Scholar] [PubMed]
- Vendruscolo, M.; Paci, E.; Dobson, C.M.; Karplus, M. Three key residues form a critical contact network in a protein folding transition state. Nature 2001, 409, 641–645. [Google Scholar] [CrossRef] [PubMed]
- Alm, E.; Baker, D. Prediction of protein-folding mechanisms from free-energy landscapes derived from native structures. Proc. Natl. Acad. Sci. USA 1999, 96, 11305–11310. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Munoz, V.; Eaton, W.A. A simple model for calculating the kinetics of protein folding from three-dimensional structures. Proc. Natl. Acad. Sci. USA 1999, 96, 11311–11316. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Clementi, C.; Jennings, P.A.; Onuchic, J.N. How native-state topology affects the folding of dihydrofolate reductase and interleukin-1ß. Proc. Natl. Acad. Sci. USA 2000, 97, 5871–5876. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Makarov, D.E.; Plaxco, K.W. The topomer search model: A simple, quantitative theory of two-state protein folding kinetics. Protein Sci. 2003, 12, 17–26. [Google Scholar] [CrossRef] [Green Version]
- Berezovsky, I.N.; Trifonov, E.N. Van der waals locks: Loop-n-lock structure of globular proteins. J. Mol. Biol. 2001, 307, 1419–1426. [Google Scholar] [CrossRef] [PubMed]
- Ittah, V.; Haas, E. Nonlocal interactions stabilize long range loops in the initial folding intermediates of reduced bovine pancreatic trypsin inhibitor. Biochemistry 1995, 34, 4493–4506. [Google Scholar] [CrossRef] [PubMed]
- Dill, K.A. Dominant forces in protein folding. Biochemistry 1990, 29, 7133–7155. [Google Scholar] [CrossRef]
- Pace, C.N.; Fu, H.; Fryar, K.L.; Landua, J.; Trevino, S.R.; Schell, D.; Thurlkill, R.L.; Imura, S.; Scholtz, J.M.; Gajiwala, K.; et al. Contribution of hydrogen bonds to protein stability. Protein Sci. 2014, 23, 652–661. [Google Scholar] [CrossRef]
- Fauchere, J.L.; Pliska, V. Hydrophobic parameters II of amino-acid side chains from the partitioning of N-Acetyl-Amino-Acid amides. Eur. J. Med. Chem. 1983, 18, 369–375. [Google Scholar]
- Ozkan, S.B.; Wu, G.A.; Chodera, J.D.; Dill, K.A. Protein folding by zipping and assembly. Proc. Natl. Acad. Sci. USA 2007, 104, 11987–11992. [Google Scholar] [CrossRef] [Green Version]
- Das, K. Antivirals targeting influenza A virus. J. Med. Chem. 2012, 55, 6263–6277. [Google Scholar] [CrossRef] [PubMed]
- Singh, J.; Udgaonkar, J.B. Molecular mechanism of the misfolding and oligomerization of the prion protein: Current understanding and its implication. J. Phys. Chem. B 2015, 54, 4431–4442. [Google Scholar] [CrossRef] [PubMed]
- Navalkar, A.; Ghosh, S.; Pandey, S.; Paul, A.; Datta, D.; Maji, S.K. Prion-like p53 amyloids in cancer. Biochemistry 2020, 59, 146–155. [Google Scholar] [CrossRef]
- Friedler, A.; Hansson, L.O.; Veprintsev, S.B.; Freund, S.M.V.; Rippin, T.M.; Nikolova, P.V.; Proctor, M.R.; Rudiger, S.; Fersht, A.R. A Peptide that binds and stabilizes p53 core domain: Chaperone strategy for rescue of oncogenic mutants. Proc. Natl. Acad. Sci. USA 2002, 99, 937–942. [Google Scholar] [CrossRef] [Green Version]
- Moreland, J.L.; Gramada, A.; Buzko, O.V.; Zhang, Q.; Bourne, P.E. The Molecular Biology Toolkit (MBT): A modular platform for developing molecular visualization applications. BMC Bioinform. 2005, 6, 21. [Google Scholar] [CrossRef] [Green Version]
Contact | Stability (kT) | Population (%) | On Structure | |
---|---|---|---|---|
C1 | 432CVIAW436 on 511VVLSF515 | −11.5 ± 0.3 | 59 | Native-like |
C2 | 432CVIAW436 on 335LCPFG339 | −10.8 ± 0.2 | 29.3 | Non-native |
C3 | 432CVIAW436 on 365YSVLY369 | −9.3 ± 0.4 | 6.5 | Non-native |
C4 | 432CVIAW436 on 349SVYAW353 | −8.7 ± 0.3 | 3.6 | Non-native |
C5 | 390LCFTN394 on 488CYFPL492 | −7.6 ± 0.4 | 1.2 | Non-native |
C6 | 398DSFVI402 on 488CYFPL492 | −6.2 ± 0.4 | 0.3 | Non-native |
C7 | 365YSVLY369 on 452LYRLF456 | −4.5 ± 0.5 | 0.1 | Non-native |
Mutation | Contact | Segment Shift | Stability (kT) |
---|---|---|---|
D364Y | C3 | 365YSVLY369 to 361CVAYY365 | −9.6 ± 0.5 |
V367F | C3 | No | −10.5 ± 0.5 |
Contact | Stability (kT) | Population (%) | On Structure | |
---|---|---|---|---|
C1 | 432CVISW436 on 511VVLSF515 | −10.7 ± 0.3 | 57.7 | Native-like |
C2 | 432CVISW436 on 335LCPFG339 | −10 ± 0.3 | 28.7 | Non-native |
C3 | 432CVISW436 on 365YSVLY369 | −8.5 ± 0.4 | 6.4 | Non-native |
C4 | 432CVISW436 on 349SVYAW353 | −8.0 ± 0.4 | 3.9 | Non-native |
C5 | 390LCFTN394 on 488CYFPL492 | −7.6 ± 0.4 | 2.6 | Non-native |
C6 | 398DSFVI402 on 488CYFPL492 | −6.2 ± 0.4 | 0.6 | Non-native |
C7 | 365YSVLY369 on 452LYRLF456 | −4.5 ± 0.5 | 0.1 | Non-native |
Contact | Stability (kT) | Population (%) | On Structure | |
---|---|---|---|---|
C1 | 431GCVIA435 on 511VVLSF515 | −6.5 ± 0.2 | 16.9 | Native-like |
C2 | 431GCVIA435 on 335LCPFG339 | −5.8 ± 0.2 | 9.3 | Non-native |
C3 | 431GCVIA435 on 365YSVLY369 | −5.6 ± 0.4 | 6.9 | Non-native |
C4 | 431GCVIA435 on 349SVYAW353 | −3.8 ± 0.3 | 1.1 | Non-native |
C5 | 390LCFTN394 on 488CYFPL492 | −7.6 ± 0.4 | 50.9 | Non-native |
C6 | 398DSFVI402 on 488CYFPL492 | −6.2 ± 0.4 | 12.6 | Non-native |
C7 | 365YSVLY369 on 452LYRLF456 | −4.8 ± 0.5 | 2.3 | Non-native |
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Bergasa-Caceres, F.; Rabitz, H.A. The Promise of Mutation Resistant Drugs for SARS-CoV-2 That Interdict in the Folding of the Spike Protein Receptor Binding Domain. COVID 2021, 1, 288-302. https://doi.org/10.3390/covid1010023
Bergasa-Caceres F, Rabitz HA. The Promise of Mutation Resistant Drugs for SARS-CoV-2 That Interdict in the Folding of the Spike Protein Receptor Binding Domain. COVID. 2021; 1(1):288-302. https://doi.org/10.3390/covid1010023
Chicago/Turabian StyleBergasa-Caceres, Fernando, and Herschel A. Rabitz. 2021. "The Promise of Mutation Resistant Drugs for SARS-CoV-2 That Interdict in the Folding of the Spike Protein Receptor Binding Domain" COVID 1, no. 1: 288-302. https://doi.org/10.3390/covid1010023